TY - JOUR
T1 - The diagnosis of severe combined immunodeficiency
T2 - Implementation of the PIDTC 2022 Definitions
AU - Dvorak, Christopher C.
AU - Haddad, Elie
AU - Heimall, Jennifer
AU - Dunn, Elizabeth
AU - Cowan, Morton J.
AU - Pai, Sung Yun
AU - Kapoor, Neena
AU - Satter, Lisa Forbes
AU - Buckley, Rebecca H.
AU - O'Reilly, Richard J.
AU - Chandra, Sharat
AU - Bednarski, Jeffrey J.
AU - Williams, Olatundun
AU - Rayes, Ahmad
AU - Moore, Theodore B.
AU - Ebens, Christen L.
AU - Davila Saldana, Blachy J.
AU - Petrovic, Aleksandra
AU - Chellapandian, Deepak
AU - Cuvelier, Geoffrey D.E.
AU - Vander Lugt, Mark T.
AU - Caywood, Emi H.
AU - Chandrakasan, Shanmuganathan
AU - Eissa, Hesham
AU - Goldman, Frederick D.
AU - Shereck, Evan
AU - Aquino, Victor M.
AU - Desantes, Kenneth B.
AU - Madden, Lisa M.
AU - Miller, Holly K.
AU - Yu, Lolie
AU - Broglie, Larisa
AU - Gillio, Alfred
AU - Shah, Ami J.
AU - Knutsen, Alan P.
AU - Andolina, Jeffrey P.
AU - Joshi, Avni Y.
AU - Szabolcs, Paul
AU - Kapadia, Malika
AU - Martinez, Caridad A.
AU - Parrot, Roberta E.
AU - Sullivan, Kathleen E.
AU - Prockop, Susan E.
AU - Abraham, Roshini S.
AU - Thakar, Monica S.
AU - Leiding, Jennifer W.
AU - Kohn, Donald B.
AU - Pulsipher, Michael A.
AU - Griffith, Linda M.
AU - Notarangelo, Luigi D.
AU - Puck, Jennifer M.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.
AB - Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.
KW - Omenn syndrome
KW - SCID
KW - Severe combined immunodeficiency
KW - leaky/atypical SCID
KW - newborn screening
KW - typical SCID
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U2 - 10.1016/j.jaci.2022.10.021
DO - 10.1016/j.jaci.2022.10.021
M3 - Article
C2 - 36456360
AN - SCOPUS:85143630502
SN - 0091-6749
VL - 151
SP - 547-555.e5
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -